MedKoo product information:

Ponatinib

Description of Ponatinib: Ponatinib is an orally bioavailable multitargeted receptor tyrosine kinase (RTK) inhibitor with potential antiangiogenic and antineoplastic activities. Multitargeted tyrosine kinase inhibitor AP24534 inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. This agent also inhibits other tyrosine kinases including those associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs); in addition, it inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3). RTK inhibition by AP24534 may result in the inhibition of cellular proliferation and angiogenesis and may induce cell death. Bcr-Abl is a fusion tyrosine kinase encoded by the Philadelphia chromosome. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    ARIAD Pharmaceuticals, Inc.

AP24534 is ARIAD’s second oncology product candidate. AP24534 is currently being evaluated in an ongoing Phase 1 clinical study in patients with hematological (blood-based) cancers, primarily chronic myeloid leukemia (CML). ARIAD expects to begin a pivotal trial of AP24534 in the second half of 2010. The primary target for AP24534 is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). AP24534 was designed using ARIAD’s computational and structure-based drug design platform to inhibit the enzymatic activity of BCR-ABL with very high potency and broad specificity. AP24534 was intended to target not only native BCR-ABL, but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including especially the T315I mutation for which no effective therapy exists.  (source: http://www.ariad.com/wt/tertiarypage/AP24534).

On December 2009, ARIAD announced positive clinical data from an ongoing Phase 1 study of its investigational, pan-BCR-ABL inhibitor, AP24534, in patients with advanced hematological cancers. The data provide strong clinical evidence of hematologic, cytogenetic and molecular anti-cancer activity of AP24534, a multi-targeted kinase inhibitor, in heavily pretreated patients with resistant and refractory chronic myeloid leukemia (CML), including those with the T315I mutation of the target protein, BCR-ABL. The data are being presented this afternoon at the 51st Annual Meeting of the American Society of Hematology (ASH) being held in New Orleans, LA. (source: http://www.news-medical.net/news/20091208/Positive-data-from-ARIAD-Pharmaceuticals-ongoing-AP24534-study-in-advanced-hematological-cancer-patients.aspx).

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2: Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-y l)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem. 2010 Jun 24;53(12):4701-19. PubMed PMID: 20513156.

3: O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. PubMed PMID: 19878872; PubMed Central PMCID: PMC2804470.

4: Noronha G, Cao J, Chow CP, Dneprovskaia E, Fine RM, Hood J, Kang X, Klebansky B, Lohse D, Mak CC, McPherson A, Palanki MS, Pathak VP, Renick J, Soll R, Zeng B. Inhibitors of ABL and the ABL-T315I mutation. Curr Top Med Chem. 2008;8(10):905-21. PubMed PMID: 18673174.